KR100858842B1 - Process for preparing optically pure oxoribose derivatives using chiral amines - Google Patents

Abstract

A method for preparing a 1-oxoribose is provided to synthesize an L-threo or a D-erythro 1-oxoribose compound selectively with improved reaction yield. A method for preparing an L-threo or a D-erythro-2,2-difluoro-2-deoxy-1-oxoribose compound represented by a formula(1) comprises the steps of: (a) hydrolyzing an ethyl 3-hydroxy propanoic acid ester compound represented by a formula(7) to prepare a 3-hydroxy propanic acid compound represented by a formula(6); (b) reacting the compound of the formula(6) with an optically pure amine-based compound selected from the group consisting of (R) or (S)-phenylethaneamine, (R) or (S)-1-(4-methylphenyl)ethaneamine, (R) or (S)-1-phenyl-1-propaneamine, (R) or (S)-1-(4-methoxyphenyl)ethaneamine, and (R) or (S)-1-(4-chlorophenyl)ethane amine to prepare an optically pure 3S- or 3R-hydroxy propanoic acid amine salt represented by a formula(5); (c) after reacting the compound of the formula(5) with a base such as NaOH and K2CO3 in an aqueous solvent to obtain 3S- or 3R-carboxylic acid from an aqueous solution layer and concentrating an organic layer, distilling it under reduced pressure to recover an amine-based compound; (d) protecting a hydroxy group of the compound of the formula(2) using a protecting group to prepare a compound represented by a formula(4); (e) reacting the compound of the formula(4) with an acid such as HCl. H2PO4 and HNO3 to prepare an erythro or a threo 5-hydroxy-1-oxo ribose compound represented by a formula(3); and (f) protecting a 5-hydroxy group of the compound of the formula(3). In the formulae, each R and R1 is independently benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, 4-t-butyl benzoyl, [1,1'-biphenyl]-4-carbonyl, 1-naphthoyl, or 2-naphthoyl; each R2 and R3 is independently C1-3 alkyl; R17 is methyl or ethyl; and R18 is H, methyl, methoxy or Cl.

Description

Process for preparing optically pure oxoribose derivatives using chiral amines

The present invention relates to a D-erythro-2,2-difluoro-2-deoxy-1-oxoribose compound represented by the following Chemical Formula I-D and L-threo-2,2-difluoro represented by the Chemical Formula I-L It relates to a method for producing a rho-2-deoxy-1-oxoribose compound.

[Formula I-D]

[Formula I-L]

Wherein R and R ₁ are each independently benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, 4- as protecting groups t-butylbenzoyl, [1,1'-biphenyl] -4-carbonyl, 1-naphthoyl or 2-naphthoyl group.

Stereochemically, the compound of the formula (I) is erythro enantio oriented downward as shown in the formula (I-D) according to the positional orientation of the hydroxy group to which hydroxyl or a protecting group is introduced as a substituent at the 3-position of the lactone ring as shown above. It can be divided into erythro enantiomer and threo enantiomer which is oriented upward as in Formula I-L, and the naturally occurring nucleoside having pharmaceutically excellent activity is generally an erythro structure. To provide.

As a representative medicine, Gemcitabin, a non-small cell lung cancer treatment agent, is an erythro compound having a structure in which a hydroxyl group at position 3 or a hydroxyl group introduced with a protecting group is oriented downward, as shown below. The compound of can be used as an important intermediate.

Therefore, in order to prepare gemcitabine, an erythro compound having a structure in which a hydroxyl group at position 3 or a hydroxyl group introduced with a protecting group is oriented downward can be effectively synthesized 1-oxoribose compound such as Chemical Formula I-D. The development of methods is very important.

Looking at a known method for preparing a 1-oxo ribose compound having an erythro structure, US Pat. No. 4,526,988 discloses 3R-hydroxy enantiomer (1) and 3S-hydroxy enantiomer (2) Process for preparing erythro compounds via 2,2-difluoro-3-hydroxy-3- (2,2-dialkyldioxoran-4-yl) propanoic acid alkyl esters mixed in a ratio of about 3 to 1 This is described.

When the 3R-hydroxy enantiomer (1) is reacted with a strong acid, as shown in Scheme 1, the dioxolane group serving as a protecting group is hydrolyzed, and the lactonation reaction proceeds, whereby the 3-hydroxy group is oriented downward. 2,2-difluoro-2-deoxy-D-erythro-1-oxoribose (3) of the structure is produced, whereas 3-S-hydroxy enantiomer (2) is reacted when 3- A treo compound (4) of the above oriented structure with the opposite hydroxyl group is produced.

Wherein R ₄ and R ₅ are each independently C ₁ to C ₃ alkyl.

Therefore, the 3R-hydroxy enantiomer (1) must be separated in a pure state to proceed with hydrolysis and lactonation reaction to selectively prepare the 1-oxoribose compound (3) having a desired erythro structure.

In this process, only 3R-hydroxy enantiomer (1) which is stereochemically suitable from a mixture of 3R-hydroxy enantiomer (1) and 3S-hydroxy enantiomer (2) in a three-to-one manner is purely Silica gel column chromatography was used for separation. However, the column chromatography method is not suitable for large scale production due to the limited size of the column and the amount of material to be loaded. Especially, the silica gel, which is a column filler, is expensive, and the development solvent must also be used in an excessive amount. It has the disadvantage of being expensive. In addition, the method has a problem that the reaction must be carried out for a long time at room temperature for 4 days to complete the lactonation reaction.

Meanwhile, US Pat. Nos. 4,965,374, 5,223,608 and 5,434,254 disclose 3-benzoyloxypropionate esters in which 3R- and 3S- are mixed in a 3-1 ratio, as shown in Scheme 2 below. ) By hydrolysis with an acid, and then azeotropically distilling water to minimize reverse reaction with the precursor to prepare a lactone ring (6) in which erythro and treo are mixed, and protect 5-hydroxy group with benzoyl. 3,5-dibenzoyloxy compound (7) was prepared, and then cooled and cooled to a low temperature of -5 ° C to 10 ° C in dichloromethane to separate and obtain only the desired erythro enantiomer (8) from the erythro and threo mixture as a precipitate. How to do this is described.

In the formula, Bz means benzoyl group.

This method is characterized in that the 3-benzoyl oxypropionate ester (5) in which 3R and 3S are mixed is used for the lactone ring reaction immediately without separation. In particular, 3,5-dibenzyl in which erythro and treo are mixed By dissolving the -1-oxo ribose compound (7) in a solvent and lowering the temperature to a low temperature, only 3,5-dibenzoyl enantiomer (8) having a desired erythro structure can be easily separated and obtained. There is this. However, this method is a highly corrosive acid used in the lactone ring reaction, and uses an excess of 3 equivalents or more of trifluoroacetic acid, an expensive and highly toxic reagent, and especially 3-benzoyl oxypropionate ester (5) as a starting material. As a result, the overall reaction yield of obtaining 3,5-dibenzoyl enantiomer (8) is very low such that it is only about 25%, which is uneconomical.

On the other hand, looking at the manufacturing method of the 3R- enantiomer and 3S-enantiomer used as precursor of the 1-oxo ribose compound, as described above, US Patent Nos. 4,526,988, 4.965.374, 5,233,608 and No. 5,434,254 describes a process in which 3R-enantiomers (1) and 3S-enantiomers (2) are produced in a ratio of about 3 to 1 via Reformatsky reaction. US Pat. Nos. 5,428,176 and 5,618,951 also include 2,2-difluoroketene silylacetal (9) as glyceraldehyde derivatives (10) and 1,3-dimethylpropylene urea (as shown in Scheme 3 below). Reacted in a specific solvent such as DMPU), to which the 3R-silylhydroxy enantiomer optionally contains a high proportion of 2,2-difluoro-β-silyloxy-1,3-dioxolane-4-propanoic acid ester ( The production method of 11) is described.

Wherein R ₆ , R ₇ , R ₈ and R ₉ are alkyl groups, and R ₁₀ and R ₁₁ are C ₁ to C ₃ alkyl groups.

According to the above method, when the reaction proceeds in a specific solvent, the ratio of the 3R-compound and the 3S-compound is 7 to 1 to 10: 1, which shows that the 3R-compound having a desired structure is greatly increased. However, this method is also a state in which 2,2-difluoro-β-silyloxy-1,3-dioxolane-4-propanoic acid ester (11) is stericly mixed with 3R- and 3S-, and is not a solid. In order to obtain a 1-oxo ribose compound having a desired erythro structure because it is obtained as a liquid, there is a problem in that the precursor 3R-propanoic acid ester enantiomer must be separated through column chromatography.

In addition, Korean Patent Application No. 10-2004-0057711 introduces a three-dimensionally large protecting group to a hydroxyl group (13), and then treats with a base to obtain a 3R-enantiomer (14) as an optically pure salt, which is locked under strong acid conditions. A method of obtaining an enantiomer (16) having an erythro structure by performing a toning reaction was shown in the following Scheme 4.

Wherein R ₁₂ , R ₁₃ and R ₁₄ are C ₁ to C ₃ alkyl groups, R ₁₅ is a phenyl group or a phenyl group with a substituent, and M is NH ₃ , Na or K.

According to the above method, the compound used as the protecting group is biphenyl-4-carbonyl chloride and the like, which is generally higher in price than the benzoyl or naphthoyl compound used as the protecting group, wherein 3R-carboxylic acid ester enan Separation of the thiomers is possible but has the disadvantage that it is not possible to obtain 3S-carboxylic acid ester enantiomers.

As described above, the conventionally known method mainly uses 3R-hydroxy enantiomer, which is a precursor, to synthesize 1-oxoribose compound having an erythro structure by hydrolyzing 3R-hydroxy group enantiomer. It is not suitable for mass production methods because it is obtained by separation through chromatography or by introducing expensive protecting groups, and it is difficult to obtain 3R- and 3S-hydroxy compounds selectively, and even though 3R- and 3S-hydroxy compounds Even when the lactonation reaction is completed in the state of the mixed mixture, erythro and threo enantiomers are mixed, so that the yield of selectively separating only erythro enantiomers from the 1-oxo ribose mixture is very low, which is uneconomical. .

It is therefore an object of the present invention to provide a process for the selective production of 1-oxoribose compounds of L-threo or D-erythro structure with improved reaction yields than conventional methods.

Another object of the present invention is to provide a novel 3S- or 3R-hydroxypropanoic acid enantiomeric compound used as an intermediate in synthesizing 1-oxoribose compounds of the treo or erythro structure in a simpler and higher reaction yield. will be.

In accordance with the above object, in the present invention, 3-hydroxy propanoic acid mixture containing 3R- and 3S-hydroxy enantiomers in a predetermined ratio is recrystallized after making 3-hydroxy propanoic acid amine salt using optically pure amine. 3R- or 3S-hydroxypropanoic acid was obtained using the above procedure, and then lactonation reaction was performed to efficiently remove 2,2-difluoro-2-deoxy-1-oxoribose compounds having an erythro or threo structure. And optionally obtainable production methods.

Specifically, in the present invention

(1) quantitatively preparing the 3-hydroxy propanoic acid compound of Formula VI by hydrolyzing the ethyl 3-hydroxy propanoic acid ester compound of Formula X with sodium hydroxide;

(2) reacting the 3-hydroxy propanoic acid compound of Formula VI with an optically pure amine based compound to prepare a compound of Formula V of an optically pure 3S- or 3R-hydroxy propanoic acid amine salt;

(3) reacting the compound of Formula V with a base in a water solvent to obtain a 3S- or 3R-carboxylic acid of Formula II, and recovering the amine based compound;

(4) protecting the hydroxy group of the compound of formula II with a protecting group to prepare a compound of formula IV;

(5) reacting a compound of Formula IV with an acid to prepare a 5-hydroxy-1-oxoribose compound of Formula III having an erythro or threo structure; And

(6) L-threo or D-erythro-2,2-difluoro-2-deoxy-1- of formula I, comprising protecting the 5-hydroxy group of the compound of formula III by conventional methods Provided are methods of preparing the oxoribose compounds:

[Formula I-D]

[Formula I-L]

[Formula II-R]

[Formula II-S]

[Formula III-D]

[Formula III-L]

[Formula IV-R]

[Formula IV-S]

[Formula Ⅴ-R]

[Formula Ⅴ-S]

[Formula VI]

[Formula Ⅶ]

Wherein R and R ₁ are each independently benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, 4- as protecting groups t-butylbenzoyl, [1,1'-biphenyl] -4-carbonyl, 1-naphthoyl or 2-naphthoyl group, R ₂ and R ₃ are each independently C ₁ to C ₃ alkyl, R ₁₇ is a methyl or ethyl group, R ₁₈ is hydrogen, methyl, methoxy or Cl.

Hereinafter, the present invention will be described in more detail.

The preparation method for the purpose of the general formula (I-D) is an erythro compound according to the present invention as shown in Scheme 5 below.

In Scheme 5, R, R ₁ , R ₂ and R ₃ are as defined above, and the compound of formula VI is a mixture of 3R- and 3S-enantiomers mixed in proportion.

Looking at the progress of the entire manufacturing process, the ester compound of formula (V) is hydrolyzed with sodium hydroxide under the conditions of tetrahydrofuran-water solvent to quantitatively obtain the carboxylic acid compound of formula (VI). The compound of formula (VI) is also a mixture of 3R- and 3S-enantiomers in a proportion, and when the compound is reacted with an optically pure amine, only pure 3R- or 3S-carboxylic acid forms salt with the amine, respectively. The production of compounds is optionally possible. The compound of formula (V) is easily separated since both 3R- or 3S- compounds are precipitated in the reaction mixture in solid form. Based on the compound of 3R-, the compound of formula V-R undergoes desalting to yield the compound of formula II-R, which is optically pure 3R-carboxylic acid. The alkali salt of the compound of R is transferred to the water layer, and the optically pure amine is transferred to the organic layer to be recovered and reused, which is economically efficient. The 3-hydroxy group of the resulting optically pure carboxylic acid compound of the formula (II-R) is a functional group having a reactive property, so it is preferentially protected, and the compound of formula (IV-R) is a protected carboxylic acid compound of the formula (II-R). When reacted with an acid, the dioxolane group is first deprotected, the water is removed at a high temperature, and the lactonation reaction proceeds to give 5-hydroxy-1-oxoribose compound of the erythro form of the formula III-D. Finally, the erythro 2,2-difluoro-2-deoxy-1-oxorai of the general object (I-D) which is the final object of the present invention by protecting the 5-hydroxy group of the compound of the general formula (III-D) by a conventional method It is possible to use optically pure amines that are stereoselective, efficient to prepare, and to produce compounds of the general formula (I-L), which are treo compounds, inverting optical activity.

As shown in the above scheme, the present invention shows that the enantiomeric mixture of formula (VI) forms an optically pure amine with a salt to selectively separate the carboxylic acid of formula (II) into 3S- or 3R-enantiomer. At this time, the optically pure salt used for separation can be recovered in the desalting process, so it is economically efficient. When the 3R-carboxylic acid of Formula II-R obtained as optically selectively pure is used as a precursor, only the erythro 1-oxo ribose compound of Formula I-D can be selectively prepared.

Compounds of formulas (V-R) and (V-S) are optically pure 3R- or 3S-carboxylic acid amine salts, which are obtained as a novel compound as a solid rather than as a liquid, which can be obtained in a high purity state without special purification. All compounds obtained in the process can also be produced as a solid, which avoids the column chromatography method. The compounds of formula II-R can be usefully used as pharmaceutical intermediates, and the compounds of formula II-S are also expected to be used as important chiral intermediates, which can be expected to expand the scope of application.

The 3-hydroxy ester compounds of formula (VII) used as starting materials in the process of the present invention may be prepared according to the methods described in US Pat. Nos. 4,526,988, 4,965,374, 5,223,608 or 5,434,254. Specifically, as shown in Scheme 6, when the aldehyde ketonide (17) and the difluoro compound (18) are mixed and the lipomethsky reaction is carried out using zinc, 3R-enantiomer and 3S-enantio A 3-hydroxy ester compound of formula (VIII) is produced in which mers are mixed in a ratio of about 3 to 1.

Wherein R ₂ and R ₃ are as defined above.

On the other hand, as shown in the following scheme 7, the 3-hydroxy ester of formula (X) mixed with R- and S-enantiomers is hydrolyzed using a base to quantitatively obtain the compound of formula (VI), and then optically pure amine When the salt is produced by the reaction with the amine, depending on the stereoselectivity of the amine, the compound of formula V, which is a 3S- or 3R-carboxylic acid amine salt, may be precipitated as a solid and separated and obtained in a pure state.

In which R ₂ , R _{3 and} R ₁₇ And R ₁₈ is as defined above.

In the present invention, the compound of formula (VI) containing 3S- and 3R-enantiomers can be separated optically pure by reacting with optically pure amine to form a salt. It has the advantage that it can be controlled by the selection of amines. The optically active amines used here include a phenyl group in the molecule and thus have a structural size (R) or (S) -phenylethanamine, (R) or (S) -1- (4-methylphenyl). Ethaneamine, (R) or (S) -1-phenyl-1-propanamine, (R) or (S) -1- (4-methoxyphenyl) ethanamine, (R) or (S) -1- (4-chlorophenyl) ethanamine is used. Among them, (R) or (S) -phenylethanamine, (R) or (S) -1- (4-methylphenyl) ethanamine, (R) or (S) -1-phenyl-1-propanamine are preferred. .

Under the conditions of Scheme 7, the reaction solvent may be a single solvent such as toluene, isopropanol, and ethyl acetate having good solubility in the compound, and preferably exhibits high purity stereoselectivity under mixed solvent conditions of isopropanol and ethyl acetate. Compounds of formula (V) are produced in high yields.

As such, the optical selectivity of the chiral amine representing (R) or (S) forms a salt with the compound of formula VI, which is an enantiomer mixture, to stereo-separately separate the compound of formula V to precipitate in solid form, thereby allowing easy separation. The compounds of formula (V) having the generated optical activity are dechlorinated to form compounds of formula (II) which are optically pure, respectively, as shown in Scheme 8 below. It can be stabilized.

Wherein R, R ₁ , R ₂ , R _{3 ,} R ₁₇ And R ₁₈ is as defined above.

In the present invention, the compound of formula V-R is easily dechlorinated to give a compound of formula II-R. At this time, the amine having optical activity in the dechlorination process is economical because it can be recovered and reused. The hydroxyl group at the 3-position of the compound of formula II-R, which is purely 3R-carboxylic acid, in the form of pure 3R-carboxylic acid can be introduced with various protecting groups, and in the protecting step, a base is used when an acid is produced. It can be neutralized by using, and examples of the base that can be used include pyridine, triethylamine, tributylamine, diisopropylethyl amine, methylpiperidine and the like, of which triethylamine is most preferred.

According to the method of the present invention, the de-chlorinated compound of Formula II-R was obtained in high yield of 80% or more, and analyzed using fluoro NMR, showed a fluorine peak of one species, resulting in more than 99% of stereoselectivity. It can be checked. In order to confirm this result more clearly, the analysis of the compound of formula (IV-R) having introduced a protecting group using an HPLC instrument, the very high purity of 99.6% or more containing less than 0.4% of the compound of formula (IV-S) is the opposite isomer (As a result, de value of 99.2% or more), it can be seen that the formula (II) having excellent stereoselectivity can be produced by the method of the present invention.

On the other hand, the compound of formula IV-R is a lactonation reaction to undergo a dehydration reaction in acid conditions as shown in Scheme 9 erythro-2,2-difluoro-2-deoxy of the general formula III-D -1-oxo ribose can be produced. The introduction of a protecting group into the hydroxyl group at position 5 of the compound enables the production of a more stable compound of formula (I-D).

Wherein R, R ₁ , R ₂ And R ₃ is as defined above.

The acid used for the lactonation reaction is preferably a strong acid having a pka of about -10.0 to about 2.0, for example, inorganic acids such as 1 N--12 N-hydrochloric acid, 1 N--9 N-sulfuric acid, methanesulfonic acid, p Organic acids such as toluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid and the like can be used. Of these, 12 N-hydrochloric acid and trifluoroacetic acid are preferred, and 12 N-hydrochloric acid is most preferred.

The acid may be used in an amount of 1 to 2 molar equivalents based on the compound of formula IV-R, with 1.1 to 1.5 molar equivalents being preferred.

Erytro 2,2-difluoro-2-deoxy-1-oxo ribose of Formula (I-D) from the erythro 5-hydroxy-1-oxo ribose compound of Formula (III-D), which is the final step of the preparation process. In the step of obtaining, the 5-hydroxy group can be protected by a conventional method, and a protecting group having a hydrophobic benzene ring or a naphthalene ring can be used as the protecting group. For example, benzoyl, phenylbenzoyl, substituted benzoyl and the like 1-naphthoyl, 2-naphthoyl, substituted 1-naphthoyl, substituted 2-naphthoyl and the like can be used, and benzoyl, 1-naphthoyl, or 2-naphthoyl is preferred.

On the other hand, 2,2-difluoro-2-deoxy-1-oxo ribose of the general formula (I-D) through the 5-hydroxy-1-oxo ribose compound of the general formula (III-D) from the compound of the general formula (IV-R) In the method for preparing, the step of separating the 5-hydroxy-1-oxo ribose compound of the general formula (III-D) and then proceeding the protection reaction, there is also a method for producing, without separating the compound of the general formula (III-D) There is also a method (in situ) prepared by proceeding the protection reaction in the same reactor. The process of directly proceeding to the 5-hydroxy protection reaction in the same reactor, in the case of progressing step by step of the yield obtained in the process of separating and obtaining the 5-hydroxy-1-oxo ribose compound of formula III-D Loss can be avoided, which is more advantageous in total yield, and can be obtained by naturally separating the 2,2-difluoro-2-deoxy-1-oxoribose of formula (I-D) into the crystalline phase, Since there is no difference in the purity and the case proceeded separately, it can be said to be a more preferable method for the production of yarn.

On the other hand, the erythro 2,2-difluoro-2-deoxy-1-oxoribose of the general formula (I-D) prepared according to the present invention is analyzed by a method using an HPLC device, the isomeric 3-position of the treo isomer No compound of formula I-L was detected, and the 1-oxoribose compound of the desired erythro structure shows a very high purity of about 99%.

As described above, the present invention showed that the compound of general formula (I-D), which is an erythro compound of D-form, can be produced with excellent yield and stereoselectivity compared to the conventional method by introducing excellent stereoselectivity, and also showing a reverse orientation. The compound of formula (I-L), which is a compound, also shows that it can be produced with excellent yield and stereoselectivity. This not only allows the preparation of intermediates of gemcitabine, an important anticancer agent known in the art, but also the production of new chiral pools.

In addition, the amine having expensive optical activity controls steric selectivity, but it is economically advantageous because the amine having optical activity can be recovered and reused in the dechlorination process.

Hereinafter, the present invention will be described in more detail with reference to the following examples, which are only intended to help the understanding of the present invention, but the scope of the present invention is not limited thereto.

Preparation Example: Ethyl 2,2-Difluoro-3-hydroxy-3- (2,2-dimethyl- [1,3] dioxoran-4-yl) propionate

13 g (200 mmol) of zinc are added to 26 mL of tetrahydrofuran, 0.51 mL of 1,2-dibromoethane is added, followed by heating to 60 ° C. for 1 minute. 0.76 mL (6 mmol) of chlorotrimethylsilane are added at 40 ° C. After 10 minutes, the internal temperature was raised to 60 ° C., 25.5 mL (200 mmol) of ethyl bromodifluoroacetate, 30.8 g (237 mmol) of 2,2-dimethyl- [1,3] -dioxolane-4-carboaldehyde ) And 39 mL of tetrahydrofuran solution are added dropwise to react with heating under reflux. The reflux is further heated for 30 minutes after the drop is complete. 65 mL of diethyl ether was added to the reaction solution and poured into 260 g of ice. 260 mL of 1 N hydrochloric acid is added thereto and stirred until the ice is dissolved. The aqueous layer is extracted three more times with 90 mL of diethyl ether. The combined organic layers are washed with 65 mL of brine and 65 mL of saturated sodium bicarbonate solution. After drying over anhydrous magnesium sulfate and filtration, the residue was distilled under vacuum of 10 Torr to obtain an organic layer separated at a temperature of 130 to 134 ℃ to give a colorless liquid 28.9 g (yield: 57%) of the title compound (R: S = 3: 1).

¹ H NMR (CDCl ₃ , 300 MHz): 1.31-1.52 (m, 9H), 2.67 (s, 1H, (R) -OH), 2.90 (d, 1H, (S) -OH), 3.7-4.4 ( m, 6H)

Example 1 (R) -3- (2,2-dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy propanoic acid (Formula VI)

23.6 g (590 mmol) of sodium hydroxide were dissolved in 300 mL of water, and ethyl 2,2-difluoro-3-hydroxy-3- (2,2-dimethyl- [1,3] dioxolane-4- 1) Propionate (R: S = 3: 1) 150 g (590 mmol) was slowly added dropwise to the dissolved in 300 mL of tetrahydrofuran. After the addition was completed, the mixture was further stirred at room temperature for 2 hours, and when the reaction was completed, the acid was treated, and then the solvent was distilled off under reduced pressure. The resulting salt is filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure, and the resulting crystals were filtered and washed with a small amount of ethyl acetate to give 126.8 g of a white solid compound (yield: 95%).

¹ H NMR (DMSO-d ₆ , 400 MHz): 4.16-4.12 (m, 1H), 4.06-4.01 (m, 1H), 3.92-3.82 (m, 2H), 1.30 (s, 3H), 1.25 (s, 3H)

¹⁹ F NMR (DMSO-d ₆ , 300 MHz): -32.37, -33.25, -35.54, -36.06

Example 2 (S) -1-phenylethanamine- (R) -3-[(R) -2,2-dimethyl-1,3-dioxolan-4-yl] -2,2-difluoro Rho-3-hydroxy propionic acid salt (Formula VR)

60 g (265 mmol) (R) -3- (2,2-dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy propanoic acid (VI) Is dissolved in 120 mL of absolute ethanol and cooled to 0 ° C. To this was slowly added dropwise 33 mL (265 mmol) of (S) -1-phenylethanamine. After stirring at 0 ° C. for 3 hours, the resulting white solid compound was filtered to give 55.2 g (yield: 60%).

¹ H NMR (DMSO-d ₆ , 400 MHz): 7.53-7.38 (m, 5H), 4.41 (q, 1H, J = 6.8), 4.18-4.13 (m, 1H), 4.07-4.00 (m, 1H), 3.92-3.84 (m, 2H), 1.53 (d, 3H), 1.33 (s, 3H), 1.28 (s, 3H)

Example 2-1: (R) -1-phenylethanamine- (S) -3-[(R) -2,2-dimethyl-1,3-dioxolan-4-yl] -2,2- Difluoro-3-hydroxy propionic acid salt (Formula VS)

60 g (265 mmol) (R) -3- (2,2-dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy propanoic acid (VI) Is dissolved in 120 mL of absolute ethanol and cooled to 0 ° C. To this was slowly added 33 mL (265 mmol) of (R) -1-phenylethanamine. After stirring at 0 ° C. for 3 hours, the resulting white solid compound was filtered to give 18.4 g (yield: 20%).

¹ H NMR (DMSO-d ₆ , 400 MHz): 7.48-7.35 (m, 5H), 4.38 (q, 1H, J = 6.8), 4.12-4.09 (m, 1H), 3.96-3.95 (m, 1H), 3.88-3.82 (m, 2H), 1.92 (d, 3H), 1.29 (s, 3H), 1.24 (s, 3H)

Example 3: (R) -3-((R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro-3-hydroxy propanoic acid II-R)

(S) -1-phenylethanamine- (R) -3-[(R) -2,2-dimethyl-1,3-dioxolan-4-yl] -2,2-difluoro-3 To 30 g (86 mmol) of hydroxy propionic acid salt (formula VR) add 60 mL of water to dissolve. To this mixture is added dropwise 34 g (86 mmol) of sodium hydroxide dissolved in 850 mL of water. After stirring for 3 hours at room temperature, it is washed with 500 mL of methylene chloride. 1N hydrochloric acid was added to the water layer to adjust the pH to about 5, and the solvent was distilled off under reduced pressure. The resulting compound is filtered and washed with ethyl acetate. Distillation under reduced pressure afforded 21.1 g of a white solid compound (yield: 99%).

To recover (S) -1-phenylethylamine separately, the layered methylene chloride solution was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The concentrated residue is distilled using a Kugeller distillation apparatus to recover most of (S) -1-phenylethylamine.

¹ H NMR (DMSO-d ₆ , 400 MHz): 4.15-4.05 (m, 1H), 4.02-3.98 (m, 1H), 3.88-3.78 (m, 2H), 1.29 (s, 3H), 1.23 (s, 3H)

¹⁹ F NMR (DMSO-d ₆ , 300 MHz): -30.80, -31.69, -35.75, -36.23

Example 4: (R) -3- (1-naphthoyloxy) -3-((R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro Rhopropanoic acid (Formula IV-R)

(R) -3-[(R) -2,2-dimethyl-1,3-dioxolan-4-yl] -2,2-difluoro-3-hydroxy propanoic acid (Formula II-R) 20 g (88 mmol) is dissolved in 100 mL of methylene chloride and cooled to 0 ° C. 18.4 mL (132 mmol) of triethyl amine was slowly added dropwise to the reaction solution. 16 mL (106 mmol) of 1-naphthoyl chloride is dissolved in 30 mL of methylene chloride and added dropwise. The reaction mixture was stirred at room temperature for 3 hours, and then washed with 100 mL of 1N hydrochloric acid, 100 mL of 5% sodium bicarbonate and 100 mL of water. It is dried over anhydrous magnesium sulfate, filtered and then distilled under reduced pressure. The reaction mixture was recrystallized from a hexane-ethyl acetate mixed solution to obtain 29 g of a white solid compound (yield: 87%).

¹ H NMR (DMSO-d ₆ , 400 MHz): 8.93 (d, 1H, J = 8.67), 8.20 (dd, 1H, J = 1.15, 7.30), 8.06 (d, 1H, J = 8.21), 7.90 (d , 1H, J = 8.16), 7.66-7.61 (m, 1H), 7.58-7.54 (m, 1H), 7.51-7.47 (m, 1H), 5.11 (quintet, 1H, J = 7.24), 4.59 (q, 1H, J = 5.71), 4.13-4.05 (m, 2H), 1.29 (s, 3H), 1.23 (s, 3H)

Example 5: 2-deoxy-2,2-difluoro-D-erythropentopuranose-1-ulose-3- (1-naphtho) -5-benzoate (Formula I-D)

(R) -3- (1-naphthoyloxy) -3-((R) -2,2-dimethyl-1,3-dioxolan-4-yl) -2,2-difluoro propanoic acid ( 20 g (53 mmol) of Formula IV-R) are dissolved in 100 mL of acetonitrile, followed by adding 6.6 mL of concentrated hydrochloric acid, followed by heating to reflux for 4 hours. After the reaction was completed, toluene was added to the reaction mixture, distillation under reduced pressure was carried out to remove the solvent and water, and then toluene was added again to distill and concentrated completely to give 2-deoxy-2,2-difluoro-D-erythropentopuranose-. Obtain 1-ulose-3- (1-naphtho) ate (Formula III-D). 100 mL of methylene chloride was added to the reaction mixture to dissolve it, and then 6.4 mL of pyridine was added thereto. 7.4 mL of benzoyl chloride dissolved in 15 mL of methylene chloride is added to the reaction solution. After stirring for 12 hours at room temperature, the mixture was washed with 300 mL of 1N hydrochloric acid, 300 mL of 5% sodium bicarbonate and 300 mL of water. It is dried over anhydrous magnesium sulfate, filtered and then distilled under reduced pressure. The reaction mixture was recrystallized from a hexane-ethyl acetate mixed solution to give 15.4 g of a white solid compound (yield: 68%).

¹ H NMR (DMSO-d ₆ , 400 MHz): 8.93 (d, 1H, J = 8.67), 8.20 (dd, 1H, J = 1.15, 7.30), 8.06 (d, 1H, J = 8.21), 8.03-8.01 (m, 2H), 7.90 (d, 1H, J = 8.16), 7.66-7.59 (m, 2H), 7.58-7.54 (m, 1H), 7.51-7.43 (m, 3H), 5.11 (quintet, 1H, J = 7.24), 4.59 (q, 1H, J = 5.71), 4.13-4.05 (m, 2H)

The enantiomer of the carboxylic acid of formula (II) can be selectively prepared in the (R)-or (S)-form by the process of the present invention, and the 2,2-difluoro of the formula (I) Each of the enantiomers of the 2-deoxy-1-oxoribose compound, the erythro or threoform, can optionally be prepared in high purity and high yield.

Claims (7)

(1) hydrolyzing the ethyl 3-hydroxy propanoic acid ester compound of formula (VII) with sodium hydroxide to prepare a 3-hydroxy propanoic acid compound of formula (VI); (2) a 3-hydroxy propanoic acid compound of formula VI is selected from (R) or (S) -phenylethanamine, (R) or (S) -1- (4-methylphenyl) ethanamine, (R) or (S ) -1-phenyl-1-propanamine, (R) or (S) -1- (4-methoxyphenyl) ethanamine, (R) or (S) -1- (4-chlorophenyl) ethanamine Reacting with an optically pure amine based compound of choice to produce a compound of formula (V) of an optically pure 3S- or 3R-hydroxy propanoic acid amine salt; (3) reacting the compound of Formula V with a base in a water solvent to obtain a 3S- or 3R-carboxylic acid of Formula II from an aqueous solution layer, concentrating the organic layer and distilling under reduced pressure to recover an amine compound; (4) protecting the hydroxy group of the compound of formula II with a protecting group to prepare a compound of formula IV; (5) reacting a compound of Formula IV with an acid to prepare a 5-hydroxy-1-oxoribose compound of Formula III having an erythro or threo structure; And (6) a L-threo or D-erythro-2,2-difluoro-2-deoxy-1-oxoribose compound of formula I, comprising protecting a 5-hydroxy group of the compound of formula III Method of preparation. [Formula I-D]

[Formula I-L]

[Formula II-R]

[Formula II-S]

[Formula III-D]

[Formula III-L]

[Formula IV-R]

[Formula IV-S]

[Formula Ⅴ-R]

[Formula Ⅴ-S]

[Formula VI]

[Formula Ⅶ]

Wherein R and R ₁ are each independently benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, 4- as protecting groups t-butylbenzoyl, [1,1'-biphenyl] -4-carbonyl, 1-naphthoyl or 2-naphthoyl group, R ₂ and R ₃ are each independently C ₁ to C ₃ alkyl, R ₁₇ is a methyl or ethyl group, R ₁₈ is hydrogen, methyl, methoxy or Cl. The compound according to claim 1, wherein the optically pure amine compound in step (2) is (R) or (S) -phenylethanamine, (R) or (S) -1- (4-methylphenyl) ethanamine, (R ) Or (S) -1-phenyl-1-propanamine of the L-threo or D-erythro-2,2-difluoro-2-deoxy-1-oxoribose compound of formula (I) Manufacturing method. The L-threo or D of formula I according to claim 1, wherein the base used in step (3) is sodium hydroxide or potassium carbonate and the acid used in the ring reaction in step (5) is hydrochloric acid, phosphoric acid or nitric acid. A process for producing an erythro-2,2-difluoro-2-deoxy-1-oxoribose compound. The process according to claim 1, wherein in step (3), the amine-based compound is acid treated under basic aqueous solution to recover with ethyl acetate or dichloromethane. The process according to claim 1, wherein the protecting group used in step (4) is benzoyl, 4-methylbenzoyl, 3-methylbenzoyl, 4-cyanobenzoyl, 3-cyanobenzoyl, 4-propylbenzoyl, 2-ethoxybenzoyl, L-threo or D-erythro-2 of formula I, characterized in that it is 4-t-butylbenzoyl, [1,1'-biphenyl] -4-carbonyl, 1-naphthoyl or 2-naphthoyl group; Method for producing a 2-difluoro-2-deoxy-1-oxo ribose compound. The process according to claim 1, wherein step (6) is performed in the same reactor without separating 5-hydroxy-1-oxo ribose compound of formula (III) in step (5). Process for the preparation of threo or D-erythro-2,2-difluoro-2-deoxy-1-oxoribose compounds. A compound represented by the following formula (V-R) or (V-S). [Formula Ⅴ-R]

[Formula Ⅴ-S]

Wherein R ₂ and R ₃ are each independently C ₁ to C ₃ alkyl, R ₁₇ is a methyl or ethyl group, R ₁₈ is hydrogen, methyl, methoxy or Cl.